ABSTRACT Type-2 diabetes (T2D) heightens the risk of heart failure, arrhythmias and sudden cardiac death, even in the absence of vascular complications. However, the underlying mechanisms are poorly understood. We propose that a critical contributor to diabetic heart disease involves myocyte Na+ dysregulation. Maintenance of cardiac Na+ homeostasis is vital for preserving heart function. Elevated myocyte Na+ concentration ([Na+]i) causes oxidative stress and augments the sarcoplasmic reticulum (SR) Ca2+ leak, thus amplifying the risk for arrhythmias and promoting heart dysfunction. Using a rat model of late-onset T2D (the HIP rat) that displays myocardial dysfunction and arrhythmias, we recently found that [Na+]i is increased in T2D hearts. Unexpectedly, higher [Na+]i seems to be caused by enhanced Na+ entry through the Na+-glucose cotransporter isoform 1 (SGLT1), a previously ignored player in cellular Na+ homeostasis. Furthermore, we found higher SGLT1 expression in hearts from patients with T2D compared to lean, non-diabetic individuals and in hearts from diabetic HIP rats vs. control rats. Cardiac-specific SGLT1 overexpression was recently shown to cause hypertrophy and left-ventricular dysfunction, while SGLT1 activation has been linked to the cardiomyopathy caused by mutations in the gene encoding the ?2 subunit of AMP-activated protein kinase. Thus, the evidence that enhanced SGLT1 activity damages the heart is mounting, but little is known about the underlying mechanisms and its role in diabetic cardiomyopathy. Based on these findings, we hypothesize that SGLT1 upregulation contributes to the multifactorial mechanism driving cardiac remodeling in T2D by perturbing myocyte Na+ dyshomeostasis. To test this overall hypothesis, we will i) assess the role of SGLT1 activation in the myocyte [Na+]i rise and consequent oxidative stress, larger SR Ca2+ leak and spontaneous afterdepolarizations in T2D, ii) test whether SGLT1 upregulation is a maladaptation of the myocardium to impaired insulin-dependent glucose uptake, and iii) assess whether SGLT1 and [Na+]i are elevated in hearts from humans with T2D. Experiments will combine fluorescence imaging, electrophysiology, biochemistry, in vivo assessment of heart function, pharmacological tools, T2D and transgenic animal models and human studies. By integrating physiological and pharmacological analyses in rat and human hearts, this project will establish whether SGLT1 activation and Na+ overload are key events in the pathology of diabetic heart disease and will identify SGLT1 as a new therapeutic target for cardiac complications in T2D patients.